Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of morbidity and mortality. Standard therapy is to attempt to contain this sympatho- excitation in the face of reduced cardiac output. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to this elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanism mediated by 1) an intra-PVN hypoxia-inducible factor (HIF-1?) mechanism: We have found that HIF-1? protein is increased in the PVN of rats with HF; A HIF-1? siRNA administered to the PVN normalizes the increased renal sympathetic nerve activity in rats with HF. 2) A renal nerve dependent mechanism: Renal denervation (RDN) is a new effective therapy for reducing sympathetic outflow in patients with hypertension. Our preliminary data shows that RDN reduces norepinephrine excretion in rats with HF, but not in sham rats, suggesting that RDN reduces sympatho-excitation in HF. Finally, as a therapeutic modality we have shown that exercise training (ExT) reduces activation of HIF-1? in the PVN and decreases neuro- humoral activation in HF. This proposal tests the hypothesis that activation of HIF-1? and/or ascending information from the renal nerves contributes to the increased sympathetic drive in HF. Furthermore, ExT, may normalizes levels of HIF-1? and/or renal afferent input to the PVN in HF. We propose to determine the underlying mechanisms for the activation of HIF-1? and/or ascending information from the renal nerves at the level of the PVN and subsequent sympatho-excitation in rats with HF. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact whole animals to studies in brain nuclei to individual neurons. We will use a variety of complementary techniques involving electrophysiological, neuroanatomical, immunohistochemical, molecular, cellular, and lentiviral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of HIF-1? and/or ascending information from the renal nerves to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.